1,2,3,5-Tetrahydroimidazothienopyrimidin-2-ones

ABSTRACT

A 1,2,3,5-tetrahydroimidazothienopyrimidin-2-one represented by the formula: ##STR1## wherein one of Z 1 , Z 2  and Z 3  is a sulfur atom and the remaining two of Z 1 , Z 2  and Z 3  represent CH, R 1  and R 2  each represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a phenyl group, a chlorine atom or, when taken together R 1  and R 2  represent an alkylene chain of 3 to 5 carbon atoms, and R 3  represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and a pharmaceutically acceptable acid addition salt thereof, which exhibit an excellent blood platelet anti-aggregatory activity and are useful as anti-thrombotic agents.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to1,2,3,5-tetrahydroimidazothienopyrimidin-2-ones represented by theformula (I): ##STR2## wherein one of Z₁, Z₂ and Z₃ is a sulfur atom andthe remaining two of Z₁, Z₂ and Z₃ represent CH, R₁ and R₂ eachrepresents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, aphenyl group, a chlorine atom or, when taken together R₁ and R₂represent an alkylene chain of 3 to 5 carbon atoms, R₃ represents ahydrogen atom or an alkyl group having 1 to 5 carbon atoms, and thepharmaceutically acceptable acid addition salts thereof.

2. Description of the Prior Art

Hitherto, anti-thrombotic agents having an imidazopyrimidine structurehave been reported in literatures. For example, W. N. Beverung et al,U.S. Pat. No. 3,932,407 discloses1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-ones represented by theformula: ##STR3## wherein R₁ represents a hydrogen atom or an alkylgroup, and R₂ and R₃ each represents a hydrogen atom, an alkyl group ora halogen atom. However, these compounds have not proved satisfactoryfor clinical use in preventing thrombosis because of their side effectssuch as hypotensive activity.

P. Blaskiewicz et al, German Offenlegungsschrift No. 2,411,273 disclosesthe compounds represented by the formula: ##STR4## but this compound isreported as having an anti-inflammatory activity. Also, C. F. Sauter etal, Monatsh. Chem., 109, 53 (1978) discloses the compounds having theformula: ##STR5## wherein R₁ and R₂ each represents --CH₃ or, when takentogether, R₁ and R₂ represent --CH₂ CH₂ CH₂ CH₂ --, but blood plateletantiaggregatory activity is not reported for the above compounds.

DETAILED DESCRIPTION OF THE INVENTION

In the formula (I) above, the partial structure ##STR6## includes thefollowing three types of condensed ring, i.e., ##STR7## which aredesignated as thieno[2,3-d]pyrimidine (A), thieno[3,4-d]pyrimidine (B)or thieno[3,2-d]pyrimidine (C), respectively.

When R₁ and R₂ jointly represent an alkylene chain, the compounds of theformula (I) are tetracyclic compounds. For example, when R₁ and R₂jointly forms a tetramethylene group --CH₂)₄ in the case ofthieno[2,3-d]pyrimidines (the partial structure (A) above), the compoundcan be represented by the formula: ##STR8## which is designated as1,2,3,5,6,7,8,9-octahydroimidazo[1,2-a][1]benzothieno[2,3-d]pyrimidin-2-one(Compound 8, hereinafter described).

The compounds of the present invention represented by the formula (I)can exist in several possible tautomeric forms, e.g.: ##STR9## whereinR₁, R₂, R₃, Z₁, Z₂ and Z₃ are as defined above.

It should be also noted that all the possible optically active andinactive compounds are included in the scope of the compounds of thepresent invention represented by the formula (I) above wherein R₃represents an alkyl group.

The compounds of the present invention represented by the formula (I)can be prepared according to the following reaction scheme: ##STR10##wherein Z₁, Z₂, Z₃, R₁, R₂ and R₃ are as defined above, and X₁, X₂ andX₃ each represents a chlorine atom or a bromine atom and R₄ represents alower alkyl group.

As seen in the above reaction scheme, a 2,4-dihalothienopyrimidinehaving the formula (II) is reduced with an alkali metal borohydride suchas sodium borohydride, lithium borohydride and the like, preferably withsodium borohydride, in an inert organic solvent such as methanol,ethanol, chloroform, aqueous tetrahydrofuran or a mixture thereof at atemperature of about 25° to about 100° C. for about one hour toovernight (about 16 hours) to give a 2-halo-3,4-dihydrothienopyrimidinerepresented by the formula (III) in high yield. The resulting compoundof the formula (III) is then reacted with an α-haloalkanoic acid alkylester, e.g., ethyl bromoacetate, ethyl α-bromopropionate and the like,in an inert organic solvent such as acetone, methyl ethyl ketone and thelike in the presence of an acid acceptor such as powdered potassiumcarbonate or sodium carbonate in an inert gas atmosphere, i.e., nitrogenor argon, while heating at a temperature of about 25° C. to about 100°C., preferably at refluxing temperature, with vigorous stirring for aperiod of about 1 to about 48 hours to give a2-halo-3-α-alkoxycarbonylalkyl-3,4-dihydrothienopyrimidine representedby the formula (IV). The resulting compound (IV) is then heated withammonia in an alcohol such as methanol or ethanol at a temperature ofabout 100° to about 150° C., preferably 120° C. to 130° C., for about 2to about 16 hours in a sealed tube filled with an inert gas, e.g.,nitrogen or argon, to obtain the desired compound of the formula (I).

The pharmaceutically acceptable acid addition salts of the compoundsrepresented by the formula (I) can be easily prepared by adding aselected nontoxic acid to a methanolic solution of the compound (I).Suitable examples of pharmaceutically acceptable nontoxic acid additionsalts are hydrochloride, hydrobromide, alkyl- or arylsulfonate,phosphate, sulfate, fumarate, maleate, succinate, tartarate, citrate andother non-toxic acid salts which are commonly used in the art.

The synthesis of the compounds of the present invention is furtherillustrated by the following Synthesis Examples. Unless otherwiseindicated, all parts, percents, ratios and the like are by weight.

SYNTHESIS EXAMPLE 1 Preparation of2-chloro-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine (Compound 1A ofFormula III)

To a solution of 4.66 g of2,4-dichloro-5,6-dimethylthieno[2,3-d]pyrimidine in 150 ml ofethanol-chloroform (1:1 by volume) was slowly added 2.32 g of sodiumborohydride with stirring. The mixture was stirred at room temperaturefor 6 hours and the solvent removed in vacuo. To the solid residue wasadded 50 ml of water and the insoluble material was filtered, washedwith water, dried, and recrystallized from benzene to give 2.05 g of2-chloro-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine, mp 170°-172°C.

Elemental Analysis:

Calc'd for C₈ H₉ ClN₂ S: C, 47.88; H, 4.52; N, 13.96; Found: C, 47.73;H, 4.47; N, 13.88.

SYNTHESIS EXAMPLE 2

In the same manner as described in Example 1 but using an equimolaramount of a substituted 2,4-dichlorothienopyrimidine having the formula(II) in place of the 2,4-dichloro-5,6-dimethylthieno[2,3-d]pyrimidineused in Example 1, the following substituted2-halo-3,4-dihydrothienopyrimidine compounds (Compounds 2A to 17A)having the formula (III) were produced. In this example, the reactionwas carried out at a temperature of 40° to 50° C. for Compounds 5A, 7A,8A, 15A and 17A, at a temperature of 50° to 60° C. for Compound 9A, at atemperature of 40°-45° C. for Compound 16A and at room temperature forthe remaining compounds.

    __________________________________________________________________________     ##STR11##                           (III)                                    Compound                                                                      No.   Z.sub.1                                                                          Z.sub.2                                                                          Z.sub.3                                                                          X.sub.1                                                                         R.sub.1                                                                              R.sub.2                                                                            mp (°C.)*                                 __________________________________________________________________________    2A    CH CH S  Cl                                                                              5-H    6-H  146-148 (dec)                                    3A    CH CH S  Cl                                                                              5-H    6-CH.sub.3                                                                         130-140[195-200(dec.)]                           4A    CH CH S  Cl                                                                              5-CH.sub.3                                                                           6-H  156-159 (dec)                                    5A    CH CH S  Cl                                                                              5-Cl   6-CH.sub.3                                                                         172-174 (dec)                                    6A    CH CH S  Cl                                                                              5-CH.sub.3                                                                           6-Cl 140-160[227-230(dec.)]                           7A    CH CH S  Cl                                                                              (CH.sub.2).sub.3                                                                          151-153 (dec)                                    8A    CH CH S  Cl                                                                              (CH.sub.2).sub.4                                                                          140-142 (dec)                                    9A    CH CH S  Cl                                                                              (CH.sub.2).sub.5                                                                          143-145 (dec)                                    10A   CH CH S  Cl                                                                              5-C.sub.6 H.sub.5                                                                    6-H  147-148 (dec)                                    11A   S  CH CH Cl                                                                              6-H    7-H  138-140 (dec)                                    12A   S  CH CH Cl                                                                              6-CH.sub.3                                                                           7-H  120-125[158-166(dec.)]                           13A   CH S  CH Cl                                                                              5-H    7-H  151-153                                          14A   CH S  CH Cl                                                                              5-CH.sub.3                                                                           7-H  168-171                                          15A   CH CH S  Cl                                                                              5-C.sub.3 H.sub.7                                                                    6-C.sub.2 H.sub.5                                                                  unclear                                          16A   CH CH S  Cl                                                                              5-CH.sub.3                                                                           6-C.sub.3 H.sub.7                                                                  unclear                                          17A   CH CH S  Cl                                                                              5-CH.sub.3                                                                           6-C.sub.5 H.sub.11                                                                 unclear                                          __________________________________________________________________________     *Generally, these compounds do not give clear melting or decomposing poin     because of the instability under heating. That is, upon heating these         compounds gradually become wet and then solidified followed by                decomposition. The figure in bracket [ ] means the decomposing point afte     the solidification.                                                      

SYNTHESIS EXAMPLE 3 Preparation of6,7-dimethyl-1,2,3,5-tetrahydroimidazo[1,2-a]thieno[2,3-d]pyrimidine-2-one(Compound 1 of Formula I)

A mixture of 6.0 g of2-chloro-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine, 5.52 g ofethyl bromoacetate and 12.5 g of powdered potassium carbonate in 300 mlof methyl ethyl ketone was heat-refluxed with stirring under a nitrogenatmosphere for 4 hours. After cooling, an insoluble inorganic salt wasfiltered off and the filtrate was concentrated in vacuo to give a crudeoil of2-chloro-3-ethoxycarbonylmethyl-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine.Because of the instability of the resulting compound, the crude oil wasused in the subsequent reaction.

A mixture of the crude oil obtained above in 50 ml of 10%ammonia-ethanol solution was heated in a sealed tube at 120°-130° C. inan oil bath for 5 hours. After cooling, the precipitated crystals werefiltered, washed with water and dried to give 3.0 g of6,7-dimethyl-1,2,3,5-tetrahydroimidazo[1,2-a]thieno[2,3-d]pyrimidin-2-one.The hydrochloride salt of the resulting compound was prepared byreacting the free compound with hydrochloric acid in methanol in a usualmanner and had a melting point of 249°-255° C. (with decomposition).

Elemental Analysis:

Calc'd for C₁₀ H₁₂ ClN₃ O: C, 46.60; H, 4.69; N, 16.30; Found: C, 46.66;H, 4.61; N, 16.29.

SYNTHESIS EXAMPLE 4

In the same manner as described in Example 3 but using an equimolaramount of a substituted 2-halo-3,4-dihydrothienopyrimidine prepared inExample 2 in place of the2-chloro-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine (1A) used inExample 3, the following compounds (Compounds 2 to 17) of the formula(I) were obtained.

    __________________________________________________________________________     ##STR12##                                                                                                              Elemental Analysis                                           Melting*         Found Values                        Comp.                    Point                                                                              Empirical   (calc'd values in bracket)          No. Z.sub.1                                                                          Z.sub.2                                                                          Z.sub.3                                                                          R.sub.1                                                                           R.sub.2                                                                            R.sub.3                                                                          (°C.)                                                                       Formula     C    H    N                         __________________________________________________________________________    2   CH CH S  6-H 7-H  H  200  C.sub.8 H.sub.8 ClN.sub.3 OS                                                              41.62                                                                              3.42                                                                              18.55                                               (dec.)           (41.83                                                                             3.51                                                                              18.30)                     3   CH CH S  6-H 7-CH.sub.3                                                                         H  233-235                                                                            C.sub.9 H.sub.10 ClN.sub.3 OS                                                             44.17                                                                              4.08                                                                              17.39                                               (dec.)           (44.35                                                                             4.14                                                                              17.24)                     4   CH CH S  6-CH.sub.3                                                                        7-H  H  252-257                                                                            C.sub.9 H.sub.10 ClN.sub.3 OS . 1/2 H.sub.2                                   O           42.69                                                                              3.98                                                                              16.77                                               (dec.)           (42.78                                                                             4.38                                                                              16.63)                     5   CH CH S  6-Cl                                                                              7-CH.sub.3                                                                         H  241-243                                                                            C.sub.9 H.sub.9 Cl.sub.2 N.sub.3 OS . 1/2                                     H.sub.2 O   37.38                                                                              3.47                                                                              14.69                                               (dec.)           (37.64                                                                             3.51                                                                              14.63)                     6   CH CH S  6-CH.sub.3                                                                        7-Cl H  220- C.sub.9 H.sub.9 Cl.sub.2 N.sub.3 OS                                                       39.16                                                                              3.47                                                                              15.12                                               (dec.)           (38.86                                                                             3.26                                                                              15.11)                     7   CH CH S  (CH.sub.2).sub.3                                                                       H  250- C.sub.11 H.sub.12 ClN.sub.3 OS                                                            49.11                                                                              3.86                                                                              15.87                                               (dec.)           (48.98                                                                             4.49                                                                              15.58)                     8   CH CH S  (CH.sub.2).sub.4                                                                       H  257-259                                                                            C.sub.12 H.sub.14 ClN.sub.3 OS                                                            50.87                                                                              4.93                                                                              14.93                                               (dec.)           (50.79                                                                             4.97                                                                              14.81)                     9   CH CH S  (CH.sub.2).sub.5                                                                       H  132-138                                                                            C.sub.14 H.sub.16 ClN.sub.3 OS                                                            52.43                                                                              5.35                                                                              14.38                                               (dec.)           (52.43                                                                             5.42                                                                              14.11)                     10  CH CH S  6-C.sub.6 H.sub.5                                                                 7-H  H  233-234                                                                            C.sub.14 H.sub.12 ClN.sub.3 OS                                                            54.79                                                                              4.22                                                                              14.02                                               (dec.)           (55.00                                                                             3.96                                                                              13.74)                     11  S  CH CH 7-H 8-H  H  >280 C.sub.8 H.sub.8 ClN.sub.3 OS                                                              42.20                                                                              3.48                                                                              18.67                                                                (41.83                                                                             3.51                                                                              18.30)                     12  S  CH CH 7-CH.sub.3                                                                        8-H  H  >280 C.sub.9 H.sub.10 ClN.sub.3 OS                                                             44.10                                                                              4.46                                                                              17.12                                                                (44.35                                                                             4.14                                                                              17.24)                     13  CH S  CH 6-H 8-H  H  262-264                                                                            C.sub.8 H.sub.8 ClN.sub.3 OS                                                              41.70                                                                              3.47                                                                              18.50                                               (dec.)           (41.83                                                                             3.51                                                                              18.30)                     14  CH S  CH 6-CH.sub.3                                                                        8-H  H  >280 C.sub.9 H.sub.10 ClN.sub.3 OS                                                             44.49                                                                              4.17                                                                              17.74                                                                (44.35                                                                             4.14                                                                              17.24)                     15  CH CH S  6-C.sub.3 H.sub.7                                                                 7-C.sub.2 H.sub.5                                                                  H  214-216                                                                            C.sub.13 H.sub.18 ClN.sub.3 OS                                                            51.67                                                                              5.96                                                                              14.03                                               (dec.)           (52.08                                                                             6.05                                                                              14.02)                     16  CH CH S  6-CH.sub.3                                                                        7-C.sub.3 H.sub.7                                                                  H  209-212                                                                            C.sub.12 H.sub.16 ClN.sub.3 OS                                                            50.88                                                                              5.69                                                                              14.51                                               (dec.)           (50.43                                                                             5.64                                                                              14.70)                     17  CH CH S  6-CH.sub.3                                                                        7-C.sub.5 H.sub.11                                                                 H  206-208                                                                            C.sub.14 H.sub.20 ClN.sub.3 OS                                                            53.39                                                                              6.30                                                                              13.63                                               (dec.)           (53.58                                                                             6.42                                                                              13.39)                     18   CH                                                                              CH S  (CH.sub.2).sub.4                                                                       CH.sub.3                                                                         240-245                                                                            C.sub.13 H.sub.15 ClN.sub.3 OS                                                            52.43                                                                              5.42                                                                              14.11                                               (dec.)           (52.24                                                                             5.51                                                                              14.02)                     19  CH CH S  (CH.sub.2).sub.4                                                                       C.sub.2 H.sub.5                                                                  220-225                                                                            C.sub.14 H.sub.17 ClN.sub.3 OS                                                            53.92                                                                              5.82                                                                              13.48                                               (dec.)           (53.81                                                                             5.91                                                                              13.24)                     __________________________________________________________________________     *Melting Point of Hydrochloride                                          

The infrared absorption spectrum and the nuclear magnetic resonancespectrum of all the compounds were found to be consistent with thechemical structure.

The compounds of the present invention have unique properties as bloodplatelet anti-aggregatory agents. These compounds are useful in theprevention of intravascular thrombosis, prevention of coronarythrombosis, prevention of transient ischemic episodes, prevention ofplatelet thrombosis in the use of prosthetic devices (artificial heartvalves, etc.) and other thrombotic complications includingthromboangitis obliterans, etc.

As stated as background of the present invention, optionally substitutedimidazo[2,1-b]quinazolines reported by Beverung et al have a potenthypotensive activity which is undesirable side effect for anticlottingtherapy. On the other hand, the compounds of the present invention donot have a hypotensive activity and more potent blood plateletantiaggregatory activity than imidazo[2,1-b]quinazolines.

EXAMPLE

The aggregometer method of Born [G. V. Born, Nature, 194, 927 (1962)]was used to assess the in vitro activity of the various compounds as toinhibition of adenosine diphosphate (ADP) and collagen (Coll) inducedplatelet aggregation. Platelet rich plasma (PRP) was separated bycentrifugation from citrated (0.313%) rat blood.

A methanolic solution of the test compound was added to the PRP, thenaggregation was induced by adding to the mixture of ADP solutioncontaining CaCl₂ or a collagen suspension prepared according to themethod described by Ashida et al [S. Ashida and Y. Abiko, Thromb. Diath.Haemorrh., 30, 528 (1975)], and the optical density of the resultingmixture was determined. Control was made by addition of methanol insteadof the above methanolic solution of the test compound, and the opticaldensity of the resulting mixture was also determined, which showed 100%aggregation. A dose response curve was drawn from the results obtainedabove and the effective concentration giving a 50% inhibition (EC₅₀) wascalculated.

The blood pressure of normal rat was measured at 5-6 hours after theoral administration at a dose of 50 mg/kg.

The most preferred compound,6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one (BL-3459)reported by Beverung et al, was tested for the biological activities atthe same time. Table I is illustrative of the blood plateletanti-aggregatory and hypotensive activities of some of the preferredembodiments of the present invention and BL-3459.

                                      TABLE I                                     __________________________________________________________________________    Inhibition of Platelet Aggregation                                                              ex vivo*    Blood Pressure                                  Compound                                                                            in vitro (EC.sub.50)                                                                      % Inhibition                                                                              % Reduction                                     No.   Coll (μM)                                                                        ADP (μM)                                                                         at 50 mg/kg(p.o)in rat                                                                    at 50 mg/kg(p.o)in rat                          __________________________________________________________________________    1     1     5     84          5 ± 3                                        4     15    19                                                                6     1.9   4.2   24                                                          8     0.1   5     57          8 ± 2                                        9     15    20                                                                11    10    85                                                                14    3.5   17    32                                                          15    2.2   3     90                                                          16    0.08  0.58  60                                                          17    0.19  2                                                                 18    0.60  48                                                                BL-3459 0.8                                                                         5     57    35 + 3                                                      __________________________________________________________________________     *ex vivo:                                                                     Blood samples were collected 2 hours after oral administration of the         compound to be tested or vehicle alone. Platelet rich plasmas were            obtained by centrifugation of the blood. Platelet aggregation was induced     by adding collagen suspension to the platelet rich plasma and was compare     with that observed with the platelet rich plasma from the control rats        given vehicle alone.                                                     

A suitable dosage level for oral administration can range from about 0.5to about 30 mg/kg in single or multiple doses along with an appropriatepharmaceutically acceptable carrier and diluent in the form of a tablet,a capsule or powder, if desired. The preferred dosage level of thecompounds of the invention for adult human is in the range of about 10to about 200 mg/day.

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A compound represented by the formula: ##STR13##wherein one of Z₁,Z₂ and Z₃ is a sulfur atom and the remaining two ofZ₁, Z₂ and Z₃ represent CH, R₁ and R₂ each represents a hydrogen atom,an alkyl group having 1 to 5 carbon atoms, a phenyl group, or a chlorineatom or, when Z₁ or Z₃ is a sulfur atom, R₁ and R₂ taken together canrepresent an alkylene chain of 3 to 5 carbon atoms, and R₃ represents ahydrogen atom or an alkyl group having 1 to 5 carbon atoms, and apharmaceutically acceptable acid addition salt thereof.
 2. A compoundrepresented by the formula: ##STR14## wherein R₁ and R₂ each representsa hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a phenylgroup, a chlorine atom or, when taken together, R₁ and R₂ represent analkylene chain of 3 to 5 carbon atoms, and R₃ represents a hydrogen atomor an alkyl group having 1 to 5 carbon atoms, and a pharmaceuticallyacceptable acid addition salt thereof.
 3. A compound represented by theformula: ##STR15## wherein R₁ and R₂ each represents a hydrogen atom, analkyl group or, when taken together, R₁ and R₂ represent an alkylenechain of 3 to 5 carbon atoms, and R₃ represents a hydrogen atom or analkyl group having 1 to 5 carbon atoms, and a pharmaceuticallyacceptable acid addition salt thereof.
 4. A compound represented by theformula: ##STR16## wherein R₁ and R₂ each represents a hydrogen atom oran alkyl group, and R₃ represents a hydrogen atom or an alkyl grouphaving 1 to 5 carbon atoms, and a pharmaceutically acceptable acidaddition salt thereof.
 5. The compound of claim 2, wherein R₁ and R₂jointly represent a tetramethylene group (--CH₂ CH₂ CH₂ CH₂ --), R₃ is ahydrogen atom and the salt is hydrochloride.
 6. The compound of claim 2,wherein R₁ and R₂ each represents a methyl group and the salt ishydrochloride.